CS245789B2 - Production method of pyridazine substituted derivatives in position 3 by substituted amino group - Google Patents

Description

These compounds have central nervous system activity and can therefore be used as active ingredients in pharmaceutical compositions.

The compounds of the invention can be represented by the general formula I

R1 is hydrogen, C1-C4alkyl, phenyl, phenyl monosubstituted by halogen or nitro or C1-C4 alkyl or C1-C4alkoxy or hydroxy, halogen-disubstituted phenyl, naphthyl, cyclohexyl, thi2-en-2-yl or thien-3-yl,

R 2 is hydrogen, C 1 -C 4 alkyl or phenyl,

R3 is hydrogen, (C1-C4) alkyl, phenyl or cyano,

R 4 represents one of the groups - COO-alkyl of 1 to 4 carbon atoms in the alkyl part and C 6 = N a

Alk represents a group (CH 2) wherein n is an integer · 2, 3, 4.

The compounds of formula I provide addition salts with mineral or organic acids. It is also within the scope of the invention to prepare addition salts of compounds of formula I with pharmaceutically acceptable acids.

The process according to the invention for the preparation of the compounds of the formula I is characterized in that the correspondingly substituted 3-chloropyridazine of the formula III

245739 in which

R1, R2 and R3 are as defined above, reacted with an excess of NH2-NH2 hydrazine hydrate, the resulting hydrazino derivative of formula III nh-nHj

N ~ N (u n in which

R 1, R 2 and R 3 are as defined above, catalytically hydrogenated, and the resulting amino derivative of general formula IV

in which

R1, R2 and R3 as defined above are reacted with a ω-halogenated compound of formula V

X — Alk — R4 (V) wherein

X represents a halogen atom,

Rd is COO-alkyl or cyano;

Alk are as defined above, and the resulting compound of formula I is optionally converted into an acid addition salt.

The process according to the invention is illustrated by the reaction scheme.

(R 4 = COO-alkyl of 1 to 4 carbon atoms in the alkyl moiety or CN).

The starting material used is 3-chlorinated pyridazine which is converted to the corresponding 3-aminopyrthazine. Since, in practice, the direct route to obtain the amine derivative is difficult to proceed via the hydrazine intermediate of formula (III) which is obtained in good yield by heating the chlorinated pyridazine of formula (II) under reflux with an excess of hydrazine hydrate. From the hydrazinated derivative of formula III, hydrogenation in the presence of a catalyst such as Raney nickel gives the amino derivative of formula IV.

By the action of a ω-halogenated ester of formula V X-Alk-R 4, wherein X is halogen, preferably bromine, Alk is as defined above, and R a is -C 1 -C 4 alkyl or cyano; an amino derivative of the formula IV gives a compound of the formula I wherein R 4 represents a C 1 -C 4 alkyl group or a cyano group. The reaction is carried out by heating the reactants in a solvent medium such as dimethylformamide at a temperature of 50 to 100 ° C.

The 3-chloropyridazines used as starting materials are known compounds or can be prepared by known methods, in particular by treating excess 2H-pyridaz-3-ones with an excess of phosphorus oxychloride.

The following examples illustrate the invention.

Example 1

3- (3-Ethoxycarbonylpropylamino) -4-methyl-6- (naphth-1-yl) -pyridazine hydrochloride of formula I wherein:

R 2 = H;

R3 = CH3;

Alk = (CH 2) 3;

R ₄ = -COOC2H5.

(a) 3-Hydrazino-4-methyl-6- (naphth-1-yl) -pyridazine

A mixture of 6.0 g of 3-chloro-4-methyl-6- (naphth-1-yl) -pyridazine with 4.8 g of hydrazine hydrate was heated at reflux for 4 hours. A precipitate formed on cooling, which was filtered off with suction, washed with water and recrystallized from methanol. Mp 206 ° C.

b) 3-Amino-4-methyl-6- (naphth-1-yl) -pyridazine

789

To a solution of 5.0 g of the hydrazine derivative prepared in a) in methanol was added 2 g of Raney nickel and the mixture was hydrogenated at room temperature under a single atmosphere pressure for 72 hours. Then the catalyst is filtered off and the solvents are evaporated to dryness under reduced pressure. The residue was recrystallized from methanol. Melting point 110 ° C.

cj 3- (3-Ethoxycarbonylpropylamino) -4-methyl-6- (naphth-1-yl) -pyridazine hydrochloride

1.18 g of the amino derivative prepared in bj are dissolved in as little dimethylformamide as possible, followed by the addition of 1.46 g of ω-bromobutyrate.

The mixture was heated at 80 degrees Celsius for 3 hours. After cooling, the reaction mixture was diluted with water, basified with 1 N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure. The oily residue was taken up with a small amount of methanol and hydrogen chloride gas was bubbled through the resulting solution until the solution had an acidic reaction. Anhydrous ether is then added and the precipitate formed is filtered off with suction. After recrystallization from isopropanol, m.p. 168 ° C.

Examples2 to 23

Using the procedure described above, but using different starting 3-chloropyridazines and / or halogenated esters, the compounds of the formula I shown in Table I are prepared.

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Table I

245739

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Example R1 R2 R3 Alk R4 Base or salt

No melting point ° C (solvent)

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Example 24

3- (3-Cyanopropylamino) -4,6-diphenylpyridazine hydrobromide of formula (I) wherein

R = R _3, Alk = (CH2) 3;

\ = S R 4 = C = N

2.47 g of 3-amino-4,6-diphenylpyridazine are dissolved in 5 ml of dimethylformamide and 1.63 g of 4-bromobutyronitrile are added. The mixture was heated at 60 ° C for 2 hours and allowed to cool. The crystals formed are filtered off with suction and recrystallized from isopropanol. Melting point 202-204 ° C.

Examples 25 and 26

Using the above procedure but using different starting 3-aminopyridazines, 3- (3-cyanopropylamino) -4-methyl-6-phenylpyridazine hydrobromide, m.p. &gt; 265 DEG C., 3- (3-cyanopropylamino) -6-phenylpyridazine hydrobromide, mp 262-264 ° C.

The results of the tests show that the compounds of the invention have an effect on the neuron by occupying a χ-aminobutyric acid reception site. They are characterized by pharmacological properties in animal experiments, so that they can be used in human medicine for the treatment of psychological neurological or neuromuscular diseases.

In particular, the compounds of the invention may be used for the treatment of mental or behavioral disorders such as depression, asthenia, Parkins disease, digestive disorders or insomnia.

The compounds of the invention may be administered orally or by injection. The pharmaceutical compositions containing them as active ingredient may be solid or liquid and take the form of, for example, tablets, pills, granules, suppositories, or injections.

The dosage may vary within wide limits, in particular depending on the type and severity of the disease and the mode of administration. In an adult, when administered orally, the daily dose is most often 0.050 to 0.500 g and can be divided, if desired, in several divided doses.

Claims (1)

A process for the preparation of amino-substituted pyridazine derivatives of the 3-position represented by the general formula I ¹ N-N (I) in which: R1 is hydrogen, C1-C4alkyl, phenyl, phenyl monosubstituted by halogen or nitro or C1-C4 alkyl or C1-C4alkoxy or hydroxy, halogen-disubstituted phenyl, naphthyl, cyclohexyl, thien-2-yl or thien-3-yl R 2 is hydrogen, C 1 -C 4 alkyl or phenyl, R3 is hydrogen, (C1-C4) alkyl, phenyl or cyano, R4 is one of —COO-alkyl having 1 to 4 carbon atoms in the alkyl moiety, and —C = N, and Alk represents a group (CH2) -, wherein n is an integer of 2, 3, 4, as well as their acid addition salts, characterized in that in the first step the appropriately substituted 3-chloropyridazine of the formula II in which: R1, R2 and R3 are as defined above, reacted with an excess of hydrazine hydrate NH2-NH2, in the second step the resulting hydrazino derivative of the general formula III R _t i Rf = J-HH-UH; N-N (1H) wherein R1, R2 and R3 are as defined above, catalytically hydrogenated, and in the third step the resulting amino derivative of formula IV is formed R1, R2 and R3 are as defined above, reacted with a ω-halogenated compound of formula (V) X — Alk — Ri (V) wherein X represents a halogen atom, R 4 is -COO-alkyl of 1 to 4 carbon atoms in the alkyl moiety or cyano; and Alk is as defined above, and the resulting compound of formula I is optionally converted into an acid addition salt.